Slow Release Pharmaceutical Composition Made of Microparticles

ABSTRACT

Pharmaceutical composition made of microparticles for the slow release of an active substance at least during a period covering the 6th month after injection of said composition, said composition comprising a group of microparticles made of a copolymer of the PLGA type which incorporate an active substance in the form of a water insoluble peptide salt; said copolymer furthermore comprising at least 75% of lactic acid and an inherent viscosity between 0.1 and 0.9 dl/g, as measured in chloroform at 25° C. and at a polymer concentration of 0.5 g/dL; said microparticles furthermore having a size distribution defined as follows: —D (v,0.1) is between 10 and 30 micrometers, —D (v,0.5) is between 30 and 70 micrometers, —D(v,0.9) is between 50 and 1 10 micrometers.

FIELD OF INVENTION

The invention relates to pharmaceutical compositions made ofmicroparticles which are used for the slow release of an activesubstance.

It more precisely relates to such compositions which comprise acopolymer of lactic and glycolic acid (PLGA) incorporating, as activesubstance, a water insoluble peptide salt.

STATE OF THE ART

Compositions as defined above are disclosed in Swiss patent CH 679 207A5.

Definitions

In the present text, the term “microparticle” has to be understood as asolid object of any shape, e.g. microsphere or microgranule, having amedian diameter of less than 250 micrometers.

The expression D (v,0.5), also mentioned as “median diameter”, meansthat 50% of the microparticles have a diameter which is less than theindicated value.

Hence, if D (v,0.5)=55 micrometers, 50% of the microparticles have adiameter which is less than 55 micrometers.

In the same way, D (v,0.1) means that 10% of the microparticles have adiameter which is less than the indicated value and D (v,0.9) means that90% of the microparticles have a diameter which is less than theindicated value.

All above values are measured by laser diffraction.

The term “microgranule” refers to an object which is the result of amilling operation on an elongated product such as an extrudate.

The term PLGA XX/YY refers to a poly(D,L lactide-co-glycolide), where XXrepresents the lactide content, and YY represents the glycolide content.The ratio lactide/glycolide being expressed in mol percent.

The term “month” refers to 28 days.

General Description of the Invention

The objective of the invention is to offer several improvements withrespect to the state of the art.

One of those improvements is to provide a continuous and efficient slowrelease of the active substance during at least a period covering the6^(th) month after injection of the composition.

To this effect the invention concerns a pharmaceutical composition madeof microparticles for the slow release of an active substance at leastduring a period covering the 6^(th) month after injection of saidcomposition, said composition comprising a group of microparticles madeof a copolymer of the PLGA type which incorporate an active substance inthe form of a water insoluble peptide salt; said copolymer furthermorecomprising at least 75% of lactic acid and an inherent viscosity between0.1 and 0.9 dl/g, as measured in chloroform at 25° C. and at a polymerconcentration of 0.5 g/dL; said microparticles furthermore having a sizedistribution defined as follows:

-   -   D (v,0.1) is between 10 and 30 micrometers,    -   D (v,0.5) is between 30 and 70 micrometers,    -   D(v,0.9) is between 50 and 110 micrometers.

In a first embodiment, the composition consists of one single group ofmicroparticles. In that case the lactide content of the PLGA is of atleast 85% and the inherent viscosity is between 0.1 and 0.4 dl/g.

A release during at least 6 months can be obtained with the compositionof this first embodiment.

The microparticles may be microspheres or microgranules.

In a second embodiment, the composition comprises a group ofmicroparticles wherein the lactide content of the PLGA is of at least85% and the inherent viscosity is preferably between 0.5 and 0.9 dl/gand more preferably between 0.63 and 0.67 dl/g.

The microparticles may be microspheres or microgranules

The group of microparticles defined in the second embodiment mayadvantageously be used for providing a slow and significant releaseduring at least a period starting from the 4^(th) month after injectionof the composition until and including the 6^(th) month.

In a third embodiment, the pharmaceutical composition furthermorecomprises another group of microparticles made of a copolymer of thePLGA type having a lactide content between 70% and 80% whichincorporates said active substance.

Both groups of microparticles may be present in a dose ratio (expressedin peptide content) close to 50:50.

The inherent viscosity of each group is between 0.5 and 0.9 dl/g.

Preferably the inherent viscosity of the other group is between 0.60 and0.70 dl/g and in particular 0.65 dl/g and the inherent viscosity of thefirst group is the same as the one defined in the second embodiment.

The microparticles of the other group may be microgranules ormicrospheres.

Advantageously both groups of microparticles are microgranules.

One group of microparticules is advantageously obtained by mixing, in asolvent-free process, said PLGA with said water insoluble peptide salt.

When two groups of microparticles are present, one group may be used toprovide a slow and significant release of the water insoluble peptidesalt during at 10 least the first three months after injection of thecomposition while the other group is used for a release starting fromthe 4^(th) month.

In a preferred embodiment the active substance is a LHRH agonisttriptorelin (used as water insoluble salt such as the pamoate saltthereof) which may be efficiently used in the treatment of prostatecancer.

The LHRH agonist triptorelin is released in an important immediateamount within hours following injection and then shows a constant andsignificant release over a long period of at least 168 days, i.e. 6months

DETAILED DESCRIPTION OF THE INVENTION

The invention is discussed below in a more detailed way with examples,the first being illustrated by the following figure:

FIG. 1 shows triptorelin, LHRH agonist, serum levels obtained with thepharmaceutical biodegradable composition of example 1,

FIG. 2 shows triptorelin, LHRH agonist, serum levels obtained with thepharmaceutical biodegradable composition of example 3,

FIG. 3 shows triptorelin, LHRH agonist, serum levels obtained with thepharmaceutical biodegradable composition of example 4,

In the following examples the viscosity is expressed in dl/g and ismeasured at a polymer concentration of 0.5 g/dl.

Example 1

A formulation of microgranules of triptorelin pamoate is prepared withthe following process.

Approximately 12% (w/w) of triptorelin pamoate is mixed withapproximately 88% (w/w) PLGA 75/25 having a viscosity of 0.65 dl/g, atroom temperature. The given mixture is duly homogenized, subjected toprogressive compression and simultaneously to a progressive heating,before extrusion. The extrudate is cut into pellets and ground at atemperature of about −100° C. The microgranules obtained after grindingare sieved below 180 micrometers. Their size distribution is defined asfollows:

D (v,0.1)=23 micrometers

D (v,0.5)=55 micrometers

D (v,0.9)=99 micrometers

A formulation of microspheres of triptorelin pamoate and PLGA 85/15having an inherent viscosity of 0.68 dl/g is prepared as follows:

Aqueous phase is prepared by mixing, under magnetic stirring, at atemperature of 40° C., 240 g of polyvinyl alcohol and 11760 g ofpurified water. In parallel, the organic phase is prepared by totaldissolution of 12 g of polymer 85/15 poly(D,L lactide-co-glycolide)(PLGA) in 45 g of ethyl acetate under magnetic stirring.

3000 mg of triptorelin pamoate are suspended in 30 g of ethyl acetateand placed under magnetic stirring. This solution is incorporated to theorganic phase previously prepared. The organic phase is then introducedin a homogenisation chamber simultaneously with the said aqueous phase.Both phases are mixed in order to obtain an emulsion and the extractionof the solvent from the organic phase and to isolate a suspension ofmicrospheres.

Finally the formulation of microspheres is recovered by filtration anddried by lyophilization.

The microspheres have a size distribution defined as follows:

D (v,0.1)=15.6 micrometers

D (v,0.5)=33.4 micrometers

D (v,0.9)=60.8 micrometers

The formulation of microspheres and the formulation of microgranules aremixed in a vial in order to have a 50:50 dose ratio of each formulation.The mixture is suspended in an appropriate aqueous medium, lyophilisedand sterilized by gamma irradiation.

The purity measured on the obtained pharmaceutical biodegradablecomposition is 98.3% and the burst evaluated in vitro (in a phosphatebuffer pH 7.4) over a 6 hours period is 22.1%.

In this example, the obtained pharmaceutical formulation is tested invivo and the animal model is the rat. The formulation as described aboveis suspended in water for injection and is administered at aconcentration dose of 18 mg/kg to 6 rats.

The LHRH agonist triptorelin of said pharmaceutical biodegradablecomposition is released in an important immediate amount within hoursfollowing injection and then shows a constant and significant releaseover a long period of at least 168 days, i.e. 6 months.

Example 2

A formulation of microgranules of triptorelin pamoate is prepared asdescribed in example 1.

A formulation of microspheres of triptorelin pamoate is prepared asdescribed in example 1 with PLGA 90/10 having an inherent viscosity of0.7 dl/g.

The microspheres have a size distribution defined as follows:

D (v,0.1)=17.6 micrometers

D (v,0.5)=39.9 micrometers

D (v,0.9)=84.2 micrometers

The formulation of microspheres and the formulation of microgranules aremixed in a vial in order to have a 50:50 dose ratio of each formulation.The mixture is suspended in an appropriate aqueous medium, lyophilisedand sterilized by gamma irradiation.

The purity measured on the obtained pharmaceutical biodegradablecomposition is 98.3% and the burst evaluated in vitro (in a phosphatebuffer pH 7.4) over a 6 hours period is 19.4%.

The LHRH agonist triptorelin of said pharmaceutical biodegradablecomposition is released in an important immediate amount within hoursfollowing injection and then shows a constant and significant releaseover a long period of at least 168 days, i.e. 6 months.

Example 3

A formulation of microgranules of triptorelin pamoate is prepared asdescribed in example 1.

Another formulation of microgranules is prepared as described in example1 with PLGA 85/15 having an inherent viscosity of 0.66 dl/g.

Approximately 20% (w/w) of triptorelin pamoate is mixed withapproximately 80% (w/w) PLGA 85/15 at room temperature. The givenmixture is duly homogenized, subjected to progressive compression andsimultaneously to a progressive heating, before extrusion. The extrudateis cut into pellets and ground at a temperature of about −100° C. Themicrogranules obtained after grinding are sieved below 180 micrometers.Their size distribution is defined as follows:

D (v,0.1)=20.5 micrometers

D (v,0.5)=51.7 micrometers

D (v,0.9)=96.9 micrometers

The 2 formulations of microgranules are mixed in a vial in order to havea 50:50 dose ratio of each formulation. The mixture is suspended in anappropriate aqueous medium, lyophilised and sterilized by gammairradiation.

The purity measured on the obtained pharmaceutical biodegradablecomposition is 98.8% and the burst evaluated in vitro (in a phosphatebuffer pH 7.4) over a 6 hours period is 45.0%.

In this example, the obtained pharmaceutical formulation is tested invivo and the animal model is the rat. The formulation as described aboveis suspended in water for injection and is administered at aconcentration dose of 18 mg/kg to 6 rats.

The LHRH agonist triptorelin of said pharmaceutical biodegradablecomposition is released in an important immediate amount within hoursfollowing injection and then shows a constant and significant releaseover a long period of at least 168 days, i.e. 6 months (see FIG. 2).

Example 4

A formulation of microspheres of triptorelin pamoate and PLGA 95/5having an inherent viscosity of 0.18 dl/g is prepared as follows:

Aqueous phase is prepared by mixing, under magnetic stirring, at atemperature of 40° C., 800 g of polyvinyl alcohol and 40 L of purifiedwater. In parallel, the organic phase is prepared by total dissolutionof 80 g of PLGA 95/5 in 334 g of isopropyl acetate under magneticstirring.

20 g of triptorelin pamoate are suspended in 100 g of isopropyl acetateand placed under magnetic stirring. This solution is incorporated to theorganic phase previously prepared. The organic phase is then introducedin a homogenisation chamber simultaneously with the said aqueous phase.Both phases are mixed in order to obtain an emulsion and the extractionof the solvent from the organic phase and to isolate a suspension ofmicrospheres.

Finally the formulation of microspheres is recovered by filtration anddried by lyophilization.

The microspheres have a size distribution defined as follows:

D (v,0.1)=17.8 micrometers

D (v,0.5)=37.1 micrometers

D (v,0.9)=74.8 micrometers

This formulation of microspheres is suspended in an appropriate aqueousmedium, lyophilised and sterilized by gamma irradiation.

The purity measured on the obtained pharmaceutical biodegradablecomposition is 99.2% and the burst evaluated in vitro (in a phosphatebuffer pH 7.4) over a 6 hours period is 10.9%.

In this example, the obtained pharmaceutical formulation is tested invivo and the animal model is the rat. The formulation as described aboveis suspended in water for injection and is administered at aconcentration dose of 18 mg/kg to 6 rats.

The LHRH agonist triptorelin of said pharmaceutical biodegradablecomposition is released in an important immediate amount within hoursfollowing injection and then shows a constant and significant releaseover a long period of at least 168 days, i.e. 6 months (see FIG. 3).

Example 5

In order to increase patients' compliance and convenience the inventorsalso developed a formulation as defined in previous example 3 whichallows one injection every 6 Months (24 Weeks). The study discussed inthis example 10 investigated the efficacy and safety of this formulationafter 2 consecutive intramuscular injections of triptorelin pamoate 22.5mg in 120 patients with advanced prostate cancer. Four-weeklytestosterone assessments were performed over 48 weeks.

Serum testosterone concentrations fell to castrate levels (51.735nmol/L) in 97.5% of the patients on D29, and 93% of the patientsmaintained castration from Week 8 to 48. Five out of 8 patients whoescaped castration had only an isolated testosterone breakthroughwithout rising PSA (Prostate Specific Antigen), indicating maintainedefficacy. Only one of these isolated breakthroughs was a true“acute-on-chronic” phenomenon after the second injection.

The median relative decreases in PSA from baseline were 96.9% at Week24, and 96.4% at Week 48, when 80.9% of patients had a normal PSA.

The type and incidence of AEs (Adverse Events) were comparable withthose observed with the registered triptorelin formulations. As withother GnRH agonists, the most frequent drug related AEs were hot flushes(71.7% of patients). The study drug was very well tolerated locally.

The study discussed above shows that Triptorelin 6-Month formulation isefficacious and safe in inducing chemical castration in patients withadvanced prostate cancer. This new convenient formulation requires only1 injection every 24 weeks, and shows comparable efficacy and safetywith the marketed 1- and 3-Month formulations.

1-14. (canceled)
 15. A method of treating prostate cancer in a patientin need thereof comprising administering to the patient a pharmaceuticalcomposition comprising microparticles comprising triptorelin pamoate,wherein the microparticles are made of poly(D,L lactide-co-glycolide)(PLGA), wherein the PLGA comprises at least 75% lactide, and wherein thetriptorelin pamoate is released from the pharmaceutical composition inan immediate amount within hours following injection and then constantlyreleased over a period of at least 168 days.
 16. The method of claim 15,wherein the composition is administered once every 6 months to thepatient.
 17. The method of claim 15, wherein the composition comprisestwo groups of microparticles.
 18. The method of claim 17, wherein atleast one of the two group of microparticles is a group of microspheres.19. The method of claim 18, wherein one group of microparticles ismicrospheres and the second group of microparticles is microgranules.20. The method of claim 17, wherein the two groups of microparticles area first group of microgranules and a second group of microgranules. 21.The method of claim 20, wherein the first group of microgranules is afirst formulation of microgranules comprising approximately 20% (w/w) oftriptorelin pamoate mixed with approximately 80% (w/w) PLGA, wherein thePLGA in the first formulation contains approximately 85% lactide and 15%glycolide and the second group of microgranules is a second formulationof microgranules comprising approximately 12% (w/w) triptorelin pamoatemixed with approximately 88% (w/w) poly(D,L lactide-co-glycolide)(PLGA), wherein the PLGA in the second formulation containsapproximately 75% lactide and 25% glycolide.
 22. The method of claim 21,wherein the first group of microgranules and the second group ofmicrogranules are mixed to have a 50:50 dose ratio of triptorelin. 23.The method of claim 15, wherein the pharmaceutical composition induceschemical castration in the patient over a six-month period of time. 24.The method of claim 15, wherein the patient has advanced prostatecancer.
 25. A method of inducing chemical castration in a patient inneed thereof comprising administering to the patient a pharmaceuticalcomposition comprising microparticles comprising triptorelin pamoate,wherein the microparticles are made of poly(D,L lactide-co-glycolide)(PLGA), wherein the PLGA comprises at least 75% lactide, and wherein thetriptorelin pamoate is released from the pharmaceutical composition inan immediate amount within hours following injection and then constantlyreleased over a period of at least 168 days.
 26. The method of claim 25,wherein the composition is administered once every 6 months to thepatient.
 27. The method of claim 25, wherein the composition comprisestwo groups of microparticles.
 28. The method of claim 27, wherein atleast one of the two group of microparticles is a group of microspheres.29. The method of claim 28, wherein one group of microparticles ismicrospheres and the second group of microparticles is microgranules.30. The method of claim 27, wherein the two groups of microparticles area first group of microgranules and a second group of microparticles. 31.The method of claim 30, wherein the first group of microgranules is afirst formulation of microgranules comprising approximately 20% (w/w) oftriptorelin pamoate mixed with approximately 80% (w/w) PLGA, wherein thePLGA in the first formulation contains approximately 85% lactide and 15%glycolide and the second group of microgranules is a second formulationof microgranules comprising approximately 12% (w/w) triptorelin pamoatemixed with approximately 88% (w/w) poly(D,L lactide-co-glycolide)(PLGA), wherein the PLGA in the second formulation containsapproximately 75% lactide and 25% glycolide.
 32. The method of claim 31,wherein the first group of microgranules and the second group ofmicrogranules are mixed to have a 50:50 dose ratio of triptorelin. 33.The method of claim 25, wherein the patient has advanced prostatecancer.